Subtle Differences among 5-HT3AC, 5-HT3AD, and 5-HT3AE Receptors Are Revealed by Partial Agonists

5-HT3 receptors are members of the Cys-loop family of ligand-gated ion channels, and, like most members of this family, there are multiple subunits that can contribute to functional pentameric receptors. 5-HT(3)A and 5-HT(3)AB receptors have been extensively characterized, but there are few studies on 5-HT(3)AC, 5-HT(3)AD, and 5-HT(3)AE receptors. Here we explore the properties of a range of partial agonists at 5-1-1T(3)AC, 5-HT(3)AD, and 5-HT(3)AE receptors following expression in Xenopus oocytes. The data show that the characteristics of receptor activation differ in the different heteromeric receptors when they are challenged with 5-HT, m-chlorophenylbiguanide (mCPBG), varenicline, 5-fluorotryptamine (5-FT), or thymol. 5-HT, 5-FT, varenicline, and mCPBG activation of S-HT(3)AC, 5-HT(3)AD, and 5-HT(3)AE receptors yields similar ECs(50)s to homomeric 5-HT(3)A receptors, but maximal responses differ. There are also differences in the levels of potentiation by thymol, which is greater at 5-HT(3)A receptors than 5-HT(3)AB, 5-HT(3)AC, 5-HT(3)AD, or S-HT(3)AE receptors. Docking thymol into the receptor indicates a different residue in the transmembrane domain could provide an explanation for these data. Overall our study suggests that 5-HT(3)AC, 5-HT(3)AD, and 5-HTvAE have distinct pharmacological profiles to those of 5-HT(3)A and 5-HT(3)AB receptors; this is likely related to their distinct roles in the nervous system, consistent with their differential association with various disorders. Thus, these data pave the way for drugs that can specifically target these proteins.